It is now well recognized that solid tumor progression is accompanied by the induction and maintenance of tumor antigen-specific T-cell tolerance through mechanisms akin to those that regulate responses to self-antigens. Unfortunately, this emerging view of tumor immunity has also raised the bar for cancer immunotherapy, since the barrier imposed by immune tolerance must be broken in order for the immune system to recognize and eliminate solid tumors expressing mainly "self". Given these sobering implications, the study of immunological tolerance, its establishment and maintenance has remained the central focus of our laboratory for the past several years. The elucidation of the cellular and molecular mechanisms involved in the decision leading to immune activation versus immune tolerance represents a critical step not only to better understand the immune system, but also to identify potential targets to overcome the remarkable barrier that immune tolerance has imposed to cancer immunotherapy. The tools and experimental models developed in the last several years will be used to systematically pursue the overall goal of this project, which is to understand the mechanisms by which Stat3 signaling in bone marrow derived APCs influence the functional outcome of antigen-specific CD4 (Specific Aim 1) and CD8 T-cells (Specific Aim 2). Furthermore, in experimental models with model tumor antigens as well as true self/tumor antigens we will evaluate whether novel strategies targeting Stat3 signaling in APCs might overcome immune tolerance and enhance the efficacy of cancer vaccines (Specific Aim 3). The knowledge to be gained in this endeavor will provide the appropriate platform for future integration of novel therapeutic approaches targeting tolerogenic mechanisms in humans with already existing active immunotherapy strategies against solid tumors.